Li and Wang Exp Hematol Oncol (2020) 9:33 https://doi.org/10.1186/s40164-020-00189-9 Experimental Hematology & Oncology

REVIEW Open Access Recent updates for antibody therapy for acute lymphoblastic Le Li and Ying Wang*

Abstract Acute lymphoblastic leukemia (ALL) is a hematologic malignancy arising from precursors of the lymphoid line- age. Conventional cytotoxic have resulted in high cure rates of up to 90% in pediatric ALL, but the outcomes for adult patients remain suboptimal with 5-year survival rates of only 30%-40%. Current immunotherapies exploit the performance of antibodies through several diferent mechanisms, including naked antibodies, antibodies linked to cytotoxic agents, and T-cell re-directing antibodies. Compared with , the application of an antibody–drug conjugates (ADC) called in relapsed or refractory (R/R) CD22­ +. ALL resulted in a complete remission (CR) rate of 81% and an overall median survival of 7.7 months with reduced toxicity. Similarly, , the frst FDA-approved bispecifc antibody (BsAb), produced a 44% complete response rate and an overall median survival of 7.7 months in a widely treated ALL population. In addition, approximately 80% of patients getting complete remission with evidence of minimal residual disease (MRD) achieved a complete MRD response with the use of blinatumomab. These results highlight the great promise of antibody-based therapy for ALL. How to reasonably determine the place of antibody drugs in the treatment of ALL remains a major problem to be solved for ongoing and future researches. Meanwhile the combination of antibody-based therapy with traditional standard of care (SOC) chemotherapy, chimeric antigen receptor (CAR) T-cell therapy and HSCT is also a challenge. Here, we will review some important milestones of antibody-based therapies, including combinational strategies, and antibodies under clinical development for ALL. Keywords: Acute lymphoblastic leukemia, Antibody–drug conjugates, T-cell redirecting antibodies, BiTE, Bispecifc T cell engager, Blinatumomab, Bispecifc antibody, Trispecifc antibody

Background R/R ALL remains grim. Treatment options are limited Te application of classical multi-agent chemotherapy previously [3, 4]. Only 20–30% of these patients achieve a in patients with ALL results in CR in more than 80% of second complete remission with standard salvage chemo- patients. About 50% of newly diagnosed patients can therapy [5]. achieve long-term disease control with further intensif- Over 100 years ago, Paul Ehrlich, a German physician cation or maintenance therapy. However 10% have initial and scientist proposed the conception of antibodies as a refractory disease [1, 2]. What’s more, many patients with “magic bullet” for selective targeting of malignant cells. ALL will subsequently relapse after remission from initial Nevertheless, it took about a century to achieve the full chemotherapy. Due to practical constraints, prognosis of potential of antibody therapy. Up to now, antibody-based therapies targeting leukemic cell surface antigens are major breakthroughs in the treatment of patients with *Correspondence: [email protected] State Key Laboratory of Experimental Hematology, National Clinical ALL, changing the traditional treatment paradigms [6]. Research Center for Blood Diseases, Institute of Hematology & Blood Based on the excellent outcomes in patients with Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union R/R B-cell ALL, this magic bullet has actually been Medical College, Tianjin 300020, China

© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativeco​ ​ mmons.org/licen​ ses/by/4.0/​ . The Creative Commons Public Domain Dedication waiver (http://creativeco​ mmons​ .org/publi​ cdoma​ in/​ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Li and Wang Exp Hematol Oncol (2020) 9:33 Page 2 of 11

incorporated into the frontline. Antibodies against some was frst extensively studied in and tumor-associated antigens (TAAs) have performed well ALL [13, 14]. Several studies have evaluated its safety and in clinical trials and have successfully come to fruition, efcacy with conventional chemotherapy [12, 15–17]. such as inotuzumab ozogamicin [7, 8] and Blinatumomab Te addition of an anti-CD20 antibody, such as rituxi- [9, 10]; more and more potential sites is also in the pro- mab, to intensive chemotherapy in adults (aged below cess of demonstration and research. Antibody-based 60 years) with ­CD20+ precursor B-ALL is considered therapies are attracting considerable critical attention. standard of care. In phase III multi-center randomized In this review, we aim to present an overview of the ef- GRAALL-2005/R [17] trial, patients < 60 years old with cacy and safety of the approved antibody-based con- Ph-negative CD20-positive B- ALL were randomized to structs used for treatment of R/R ALL, and the ongoing receive 16–18 doses of rituximab in addition to standard researches of diferent formats, then give a brief intro- chemotherapy. Te 2-year EFS was 65% in the rituximab duction of combinational strategies. group versus 52% in the control group (p = 0.04). Te Monoclonal antibodies can be classifed into three 2-year OS was 71% in the rituximab group versus 64% in main groups according to their construction: naked anti- the control group, although not statistically signifcant bodies, ADCs, and T-cell re-directing antibodies. Tese (p = 0.10). Sensitivity analyses with monitoring during agents bind to known surface cell antigens present on HSCT showed a statistically signifcant improvement in the ALL blasts and mediate cell death through a vari- OS in the rituximab group (hazard ratio, 0.55; p = 0.02). ety of mechanisms that are specifc to their target anti- Tis study demonstrated that addition of rituximab to gens and construct. Naked antibodies bind directly to conventional chemotherapy improved the patient out- the surface cell antigen and mediate cell lysis through come with B-cell ALL in terms of EFS for a certainty. antibody-dependent cellular cytotoxicity (ADCC), com- is a second-generation anti-CD20 mono- plement-dependent cytotoxicity (CDC) and induction clonal antibody, that leads to more efective ADCC and of apoptosis. A variety of ADCs has also been developed CDC than rituximab, which is associated with its binding that link a to a potent cytotoxin or to a proximal small loop on the CD20 antigen [18, 19]. radioisotope, knows as payloads. Tese conjugated anti- In an ongoing phase II study, ofatumumab has been simi- bodies are internalized upon binding to the surface cell larly studied in combination with hyper-CVAD in newly marker, leading to cell death through the release of the diagnosed CD20 positive B-ALL patients (CD20 expres- toxic payload. Bispecifc antibodies (BsAb) have attracted sion > 1%) [20]. However, whether ofatumumab improves signifcant attention in antitumor immunotherapy [11]. long-term outcomes compared with rituximab in wider Based on the structure of the Fc domain, BsAb can be settings needs long-term follow up. classifed into two types: IgG-like format and Fc-free Given the fact that nearly 90% of B lymphoblasts in format. BsAbs engage two diferent target epitopes and ALL express CD22, which rapidly internalized upon consist of variable domains linked together to form a sin- ligand binding [13], researchers are now focusing on it. gle-chain antibody, such as BiTEs, dualafnity re-target- Epratuzumab is an anti-CD22 monoclonal antibody with ing antibodies (DART) and tandem diabodies (TandAb). a very limited therapeutic efect. In pediatric patients, Tese antibodies lack the Fc region, therefore they are its efect in combination with chemotherapy is not obvi- smaller in size. Although their half-life is shorter than ous [21, 22], and is currently undergoing an international other types of antibody constructs, they usually have bet- phase 3 trial (NCT01802814). ter tissue penetration and lower immunogenicity. Addi- Te latest analyses show that CD38 is a promising tionally, bispecifc antibodies (BsAbs) with a functioning therapeutic antigen for acute leukemia [23]. Daratu- Fc region, which can attract efector cells expressing FcR mumab, a recombinant anti-human CD38 monoclonal like macrophages, are called “trifunctional” (e.g. Triom- antibody approved by the FDA for the treatment of abs). If BsAb has two or more binding sites for two difer- myeloma, has also been suggested to be efective in the ent specifcities, it is referred to as bivalent, trivalent or treatment of acute leukemia. It not only exploits clas- even tetravalent. Figure 1 schematizes brief mechanisms sical ADCC mechanisms depending on CD38 expres- of diferent antibodies that will introduce in detail. sion on tumor cells, but also plays a multifaceted [24] immuno-modulatory role (recently reported in MM Naked antibodies patients) [25]. Evidence of the role of Monoclonal antibodies for many established cell surfaces in T-ALL has been demonstrated in preclinical stud- which are highly expressed on ALL blasts had achieved ies using mouse models [26, 27]. According to the precise results. Te CD20 antigen can be found in about latest literature, there is one case of successful remis- 30–50% of B-cell ALL, while CD19 and CD22 are pre- sion induced by daratumumab in a patient with Ph­ + sent on the cell surface in over 90% of B-cell ALL [12, 13]. refractory B-ALL [28], and another one case report of Li and Wang Exp Hematol Oncol (2020) 9:33 Page 3 of 11

Fig. 1 Schematic mechanisms of some popular antibodies. Classical monoclonal antibodies, antibody–drug conjugates, bi-specifc antibodies (with or without Fc domain) and tri-specifc antibodies. In addition, according to the Fc domain, BsAbs can be divided into two types: IgG-format molecules and non-IgG-format molecules (e.g. BiTE)

eradication of MRD in a patient with advanced relapse tumor burden cases, similarly to blinatumomab in after allo-HSCT [29]. Te application of daratumumab B-ALL [32]. for the eradication of MRD in high-risk advanced relapse of T-cell or CD19/CD22-negative acute lymph- Antibody–drug conjugates oblastic leukemia has been demonstrated. Cerrano et. As a warhead used in the clinical‑stage for ALL: al recently described [30] the clinical and immuno- inotuzumab ozogamicin (IO) modulatory efects of daratumumab in a 44-year-old CD22 is a 135 kDa sialoglycoprotein that is generally con- relapsing T-ALL patient after allo-HSCT(according to sidered as an important B-lineage surface antigen. Tere published MM schedule [31]). Te patient remained CR are further studies conducted to better understand the with MRD-negativity for 16 months after the applica- immunobiology and metabolism of CD22 to aid in the tion of daratumumab. Terefore, the anti-CD38 anti- development of CD22-directed therapies for the treat- body is considered to achieve a better outcome in low ment of B-lymphoid malignancies. In a fow-cytometric Li and Wang Exp Hematol Oncol (2020) 9:33 Page 4 of 11

cell surface expression study of 104 ALL cases, there median OS was 7.7 versus 6.7 months (p = 0.04), respec- was a signifcant positive correlation between CD22 tively. Signifcantly higher remission rates were observed expression and ALL at 96% (considering the expression in all patients regardless of bone marrow blast percent- of > 20% in blast cells as positive) [33]. CD22 undergoes age, CD22 expression, prior HSCT, or karyotype, except constitutive endocytosis into B-cells and is not shed into for Ph-positive ALL patients who did not preferentially the microenvironment after antibody ligation, and it is beneft from the 2 therapies. Hepatotoxicity was the most then degraded in lysosomes and not recycled back to the common event in patients treated with IO. Veno-occlu- cell surface. Terefore, research indicates that CD22 is sive disease (VOD) was reported in 15 patients (11%) in an attractive target in the development of novel targeted the IO group. Most cases 10–15 patients occurred after therapies. HSCT and the median time of development was 16 days IO binds to CD22 and is internalized to release cali- (3–39). In August 2017, based on the data of the INO- cheamicin, a cytotoxic payload that binds to double- VATE study, the US FDA approved IO (BESPONSA) for stranded DNA. Upon antigen binding, the ALL cell the treatment of adults with R/R B-cell precursor ALL endocytoses IO and the acidic environment of the lyso- (BCP-ALL). some dissolves the linker protein, thus releasing the calicheamicin toxin intracellularly. In vitro studies have ADCs under clinical development for ALL shown that cells required CD22 expression for the uptake Currently, new antibody-based therapies are in the early of IO, but continuous saturation of the receptor was not stage of development, most of which target three major a necessity for apoptosis, suggesting that multiple low IO antigens, namely CD19, CD20, and CD22, but also CD25, dosages may be efective [34]. CD123, and CD38. Te vast majority of antibodies can bind to diferent cytotoxins (Table 1). Single‑agent: an INO‑VATE study IO was subsequently compared with standard salvage in Targeting CD19 the INO-VATE study, a phase III study of 326 patients (also ADCT-402) is an ADC with R/R B-ALL [35]. All patients aged ≥ 18 years with comprising of a humanized anti-CD19 antibody, sto- R/R CD22-positive ALL were randomly allocated in a 1:1 chastically conjugated through a cathepsin-cleavable ratio to receive either IO or combination cytotoxic chem- valine-alanine linker to SG3199, a pyrrolobenzodiaz- otherapy. IO was given at a 1.8 mg/m2 per cycle in a frac- epine (PBD) dimer-containing toxin. Te mechanism of tionated weekly dosing (0.8 mg/m2 on day 1 and 0.5 mg/ SG3199 for DNA crosslinking contributes to persistence m2 on days 8 and 15 per cycle). Te chemotherapy regi- in cells [36], and SG3199 has had picomolar antitumor mens were either the FLAG regimen, a high-dose cyta- activity against human hematologic tumor cells in in- rabine-based regimen, or cytarabine plus mitoxantrone. vitro studies [37]. In preclinical studies, loncastuximab Te CR/CR with incomplete hematologic recovery tesirine has shown potent dose-dependent antitumor (CRi) and MRD negativity rate was signifcantly higher activity against CD19-expressing B-cell malignancies in in the IO arm with CR/ CRi rates of 81 versus 29% both in-vitro and in-vivo preclinical models [38]. A phase (p < 0.001) and an MRD negativity rate of 78 versus 28% I study (NCT02669264) to assess the safety, tolerability, (p < 0.001) by fow cytometry. Compared with the SOC PKs, immunogenicity, and preliminary clinical activity group, more patients who received IO underwent HSCT of loncastuximab tesirine in adults with R/R B-ALL [39], (41 versus 11%; p < 0.001). Te median PFS for IO and demonstrated acceptable safety and tolerability profle in for SOC was 5 versus 1.8 months (p < 0.001), and the patients with R/R B-ALL. However, a formal assessment

Table 1 Novel ADCs in early clinical research in ALL Antibody Target Payload Phase of trial Setting Identifer

ADCT-602 CD22 PBD-dimer toxin I/II R/R ­CD22+ NCT03698552 ADCT-402 (loncastuximab tesirine) CD19 PBD-dimer toxin I R/R NCT02669264

SGN-CD19A () CD19 monomethyl aurista- I R/R ­Ph− NCT01786096 tin F (MMAF)

ADCT-301 (camidanlumab tesirine) CD25 PBD-dimer toxin I R/R ­CD25+ AML/ALL NCT02588092

IMGN632 CD123 IGN I R/R ­CD123+ NCT03386513

AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, B-ALL B-cell acute lymphoblastic leukemia, Ph − Philadelphia chromosome negative, Ph + Philadelphia chromosome positive, R/R relapsed/refractory, T-ALL T-cell acute lymphoblastic leukemia Li and Wang Exp Hematol Oncol (2020) 9:33 Page 5 of 11

of the potential efect of loncastuximab tesirine was not T cell‑redirecting antibody performed in the trial because of the early termination The frst and only approved BiTE: Blinatumomab of the study (slow accrual of dose escalation). one patient BiTE is a relatively mature kind of BsAb obtained by experienced DLT and three of all 35 patients (8.57%) ligating anti-CD3 single-chain Fv (scFv) with its coun- received CRs as a response to loncastuximab tesirine, and terpart of various anti-tumor cell surface antigens two of the three patients had received previous CD19- through peptides, which can simultaneously bind T directed therapy (Blinatumomab was discontinued due to cells to tumor cells and induce continuous attack of its toxicity). Further investigation in clinical trials would the target without T-cell apoptosis or anergy. Blinatu- be more encouraging. momab is the frst FDA and EMA approved BiTE for the treatment of R/R ALL. It is a small (55 kDa) single- chain peptide that links two antibody variable regions Targeting CD25 directed against CD3 and CD19. Cytolytic synapsis Human CD25, the α-chain of the heterotrimeric inter- formed, T cells can be activated without costimulatory leukin-2 receptor, is a critical component in regulating molecules. Blinatumomab results in the proliferation of the immune system [40–42], and its expression is lim- CD8-positive T cells with a predominance of cytotoxic ited to activated T cells, B cells, and regulatory T cells ­CD8+ T efector memory (TEM). (T-reg). Te expression of CD25 on the surface of AML and ALL blasts is associated with the failure of induc- tion treatment, increased risk of relapse, and short over- Single‑agent: TOWER study and BLAST study all survival [40]. Te concept and safety of targeting Blinatumomab has shown encouraging results in phase I/ CD25 in malignancies have been established, and there II clinical trials in R/R B-cell ALL, especially in the set- is a large number of therapeutic approaches at diferent ting of low tumor burden [49, 50]. Te pivotal phase III stages of development, including immunotoxins, radio- multicenter, open-labeled international study, TOWER, immunoconjugates, and ADCs [43]. Camidanlumab demonstrated obvious advances in adults with R/R tesirine (ADCT-301) is an ADC comprising a human- B-ALL with higher CR rates (34 vs. 16%; p < 0.001), ized anti-CD25 antibody stochastically conjugated to greater MRD negativity (76 vs. 48%) and longer median SG3199, a PBD dimer mentioned above. Results of the OS (7.7 and 4 months; p = 0.001) in comparison to SOC data from part1 of a phase I study, though limited, that chemotherapy [51]. Tis beneft was seen irrespective of conducted at 11 centers across the US in patients with age, condition of prior therapies, previous HSCT, or the CD25-positive R/R AML or ALL (NCT02588092) have percentage of bone marrow blasts, but was more marked been recently presented [43–45]. No additional adverse in the frst salvage (median OS 11.1 vs. 5.3 months). For events (AEs) of interest for camidanlumab tesirine were blinatumomab in Ph­ − ALL [49] or ­Ph+ ALL [52], the two observed in this study. Remarkable outcome emerged crucial factors that infuence the CR rate are the num- that AEs of polyradiculopathy/Guillain-Barré syndrome ber of prior therapies (salvage chemotherapy) and tumor observed with camidanlumab tesirine in the R/R classical burden (measured by the percentage of bone marrow Hodgkin’s lymphoma (HL) population were not seen in blast cells). Te two adverse events of interest are neuro- this study [43]. toxicity and cytokine release syndrome (CRS), which are reported in 10 and 5% of cases, respectively. Targeting CD123 Another signifcant result came from a multicenter, CD123, the alpha chain of the interleukin-3 (IL-3) recep- phase II BLAST study [32], aiming to evaluate the safety, tor, is the major low-afnity subunit of the IL-3 recep- efcacy and tolerability of blinatumomab in adult with tor and promotes high-afnity binding to IL-3 when MRD-positive BCP-ALL. All 116 patients were in CR (65 frst CR) after 3 intensive chemotherapy treatments and co-expressed with the beta subunit. IL-3 is mainly pro- ≥–3 duced by T lymphocytes, and it regulates the production MRD was ≥10 . Te primary endpoint was MRD nega- of hematopoietic cells by stimulating cell cycle progres- tivity after one cycle. A total of 91 of the 113 evaluable sion, diferentiation, and inhibiting apoptosis. Early patients obtained a complete MRD response of 78% (82 studies have shown that IL-3 plays a key role in the devel- patients were attained after the frst cycle). Te medians opment of leukemia by allowing leukemia cells to escape of RFS and OS for the group were 18.9 and 36.5 months, programmed cell death and grow autonomously [46]. respectively. Te tolerability of blinatumomab was simi- Te potential of CD123-targeted drugs in ALL remains lar to that reported in previous trials. Based on these largely unexplored. Data on the association between results, the regulatory authorities in the US extended the CD123 expression and B-ALL are limited. Nevertheless, authorization of blinatumomab to MRD-positive BCP rewarding attempts have already been made [47, 48]. (Table 2). Li and Wang Exp Hematol Oncol (2020) 9:33 Page 6 of 11

Table 2 Safety and efcacy results from clinical trials of blinatumomab

Type R/R Ph­ − R/R Ph­ + MRD+ Ref [44] [43] [45] [46] [48] [49]

Regimen BLN BLN BLNvs SOC BLN BLN BLN Capacity 36 189 405 45 21 116 second salvage 21% 39% 45% 82% 36% ≥ Response CR/CRh: 69% CR/CRh: 43% CR: 34% CR/CRh/ CR: 31% CR/CRh: 36% MRD response: MRD CRi: 44% 80% response: 78% OS (median) 9.8 6.1 7.7 7.1 – 36.5 Grade3 neurotoxity 16% 11% 9% 7% 19% 13% + Grade3 CRS 6% 2% 5% 0% 0% 2% + MRD minimal residual disease, CRS cytokine release syndrome, Ref. reference number, R/R relapsed/refractory, Ph Philadelphia chromosome, BLN blinatumomab, SOC standard of care, CR complete response, CRh complete response with partial hematologic recovery, CRi complete response with incomplete hematologic recovery, OS overall survival

To date, several mechanisms have been addressed to and pharmacokinetics of IGM-2323 in subjects with R/R explain resistance or relapse after blinatumomab strate- NHL. Terefore, its potential to cure more hematological gies. Tese factors comprise the presence of extramedul- malignancies, like acute leukemia, could be anticipated. lary disease [53], higher leukemia burden on treatment, PD-L1 expression (54) and loss of CD19 expression on Other potential forms of BsAbs leukemic cells [55]. Given the superior activity of blina- Due to the small size of blinatumomab, it can reach the tumomab in R/R B-ALL and the ­MRD+ settings, current T cells and target membranes quickly, which also leads to investigations are ongoing to evaluate blinatumomab its rapid clearance from the circulation [56, 57]. Tere- as a component of the initial treatment strategy (eg, fore, BiTE should be administered continuously and at NCT03914625). Similar studies using blinatumomab in high concentrations (15–28 gperday) to recruit and acti- other settings are also in the pipeline; for example, post- vate large numbers of suboptimal T cells to achieve the transplant maintenance to prevent relapse after HSCT half-maximal target cell lysis [58]. Te antibody is admin- (NCT02807883), which has a parallel in the use of post- istered as a 4-week continuous intravenous (IV) infusion transplant TKI (tyrosine kinase inhibitor) therapy in ­Ph+ to maintain efective therapeutic serum concentration B-ALL. [56], which directly increases the cost of treatment. Te single polypeptide chain structure that enhances BiTE T cell‑redirecting antibodies under clinical development antibody-antigen recognition comes at the expense of for ALL increased aggregation and decreasing protein stability IGM-2323 is a CD20/CD3 bispecifc IgM antibody [59, 60]. In response to these issues, dual-afnity re-tar- designed to treat patients with B cell Non-Hodgkin’s lym- geting proteins (DARTs) have been developed. phoma (NHL) and other B cell malignancies. Its potential DART consists of two Fv fragments that form two antineoplastic activity manifests itself. Instead of bind- unique antigen binding sites when they heterodimerize. ing to one or two TAA molecules on the surface of the Fv1 consists of VH from antibody A and VL from anti- cancer cell, IGM-2323 has 10 binding units to CD20 and body B, whereas Fv2 is formed of VH from antibody B one binding unit to CD3. Terefore, it can bind to CD20- and VL from antibody A. Unlike BiTEs antibodies which expressing cancer cells with higher avidity in comparison are linked via a polypeptide linker, this combination with the IgG type. Tis may include those clinical cir- allows DART to mimic natural interactions within IgG cumstances in which CD20 expression has been reduced molecules. Compared to BiTE, DART molecules can also due to prior treatment with other anti-CD20 antibodies, maintain potency when administered both in vitro and such as rituximab. Two mechanisms are employed aimed in vivo [61, 62]. Moore et al. [60] compared the in vitro at killing cancer cells. One is T cell-directed cellular ability of CD19xCD3 DART and BiTE molecules to kill cytotoxicity (TDCC) and the other is CDC. Compared B-cell and found that DART molecules con- to IgG format BiTEs, IGM2323 appears to induce less sistently outperformed BiTE molecules. cytokine release, and less CRS, associated with TDCC. Compared to natural antibodies, the renal clearance Currently, there is only one study reporting the safety of small-sized scFv lacking the Fc region is signifcantly Li and Wang Exp Hematol Oncol (2020) 9:33 Page 7 of 11

higher. Tandem diabodies (TandAbs) have emerged to Novel combinational strategies address the size problem. Tese tetravalent bispecifc Ph‑negative ALL antibody provides two binding sites for each antigen to Currently, several novel antibodies can provide efective maintain the avidity of each natural bivalent antibody salvage therapy for patients with R/R ALL, with higher [63, 64]. Furthermore, the molecular weight of Tand- response rates and OS rates compared with conven- Abs (approximately 105 kDa) exceeds the threshold of tional chemotherapy. Early addition of these new agents frst-pass renal clearance, hence its half-life is longer to the frontline can be considered promising to further compared to other non-Fc antibody constructs [63, 65]. consolidate the therapeutic efcacy of relevant patients, Clinical trials are underway correlating with two TandAb while reducing the number of cytotoxic chemotherapies format drugs—AFM13 (CD30xCD16) for NK cell recruit- required to achieve a durable response. Such regimens ment and AFM11 (CD19xCD3) for T cell recruitment. can improve tolerability and reduce treatment-related morbidity and mortality. In R/R cases, correlative com- Three is promising for T‑cell redirecting therapy bination studies are ongoing to improve the results of the With the evolution of antibody technology, CD28 co- single-agent application of Blinatumomab and IO. Some stimulation provides a novel choice for therapeutic trials have corroborated this, especially for patients in interventions. Recently, Wu et al. [66] published a devel- frst salvage [67]. Although HSCT currently remains the opment about tri-specifc antibody. Te antibody has treatment of choice in the second remission, combination three targets: cancer cells, receptors that activate T cells regimens with new agents have shown a strong potential and costimulatory signals that promote long-lasting for alternation. Encouraging results have been published T cell activity against cancer cells. It is based on bispe- to indicate the efcacy and safety of combinational strat- cifc antibody technology, and the innovation lies in the egies for Ph-negative ALL (Table 3). introduction of costimulatory domain that promotes enhanced T cell activation, that is, simultaneous target- Ph‑positive ALL: chemo‑free? ing of CD3 and CD28 molecules on the surface of T cells and CD38 molecules on the surface of cancer cells. CD28 Blinatumomab was demonstrated in the phase II is a member of the immunoglobulin super family (IgSF), ALCANTARA study to be safe and efective in patients which is expressed on the surface of naive T cells under with Ph-positive ALL [52]. In combination with TKIs, physiological conditions and binds to B7 molecules on mainly ponatinib, grouped with blinatumomab has been the surface of antigen-presenting cells (APCs), provid- demonstrated to be safe and efective in a small case con- ing an important second signal for T cell activation. Tis sisting of 15 patients from MD Anderson Cancer Center. plays a key role in T cell proliferation and the production Te CR rate and molecular response was 50 and 75% of cytokines such as IL-2, ensuring T cells activate cor- respectively [68]. Ponatinib is a potential TKI for patients rectly in spatial–temporal patterns. Lack of the second with Ph-positive ALL [69]; however, its hepatotoxic- signal from costimulatory molecules will leads to a state ity limits its potential for cooperation with IO. Accord- of non-response, also termed as anergy. ingly, researchers combine IO with less hepatotoxic TKIs, To confrm the enhanced activity from costimulatory bosutinib for instance. In a phase I/II trial, patients with domain of trispecifc antibodies, the group made versions R/R Ph-positive ALL or lymphoblastic phase chronic of diferent combinations of all three binding domains myelocytic leukemia(CML), combination of bosutinib that were mutated and tested them in "humanized" with IO strategy showed exciting efcacy [70]. It must be model mice with human T cells and human myeloma mentioned that patients with T315I mutations are not eli- cells. Functional targeting of the CD28 domain enhanced gible for the criteria of the study. Patients were adminis- tered bosutinib at a dose of 300–500 mg with IO at a dose T cell activation above that showed using antibodies 2 lacking this domain. Te results found that both prolifer- of 0.5–0.8 mg/m on days 1, 8 and 15, given in 4-weekly ation of T cells and expression of the anti-apoptotic pro- cycles. 14 patients, with a median age of 62 years, were tein Bcl-xL were signifcantly enhanced, supporting the treated in the study. Overall, 79% of patients achieved authors’ hypothesis, that is, having costimulatory signals CR/CRi, and 91% of responders achieved a complete would prevent T cell apoptosis, even at the lowest anti- cytogenetic response, 73% achieved MRD negativity. body dose tested. Te method of introducing the costim- No BCR-ABL was detected in 55% (6/11) of respond- ulatory domain has also been applied in chimeric antigen ers. Te median OS and EFS were 8.2 and 8.1 months, receptor T-cell (CAR-T) therapy at the same time. Te respectively. main limitation of this study is the cytokine release syn- Te GIMEMA group has recently updated their results drome (CRS) resulting from highly stimulated immune from D-ALBA [71], the frst chemo-free induction-con- system. solidation protocol including the sequential use of TKI/ Li and Wang Exp Hematol Oncol (2020) 9:33 Page 8 of 11

Table 3 Important combinational studies for ­Ph− ALL

Type Frontline Ph­ − ALL R/R Ph­ − ALL Ref [64] [65] [66] [67] [68]

Rigemen Sequential hyper- Mini-HCVD IO BLN SWOG 1318: SWOG 1312: CVP IO Mini-HCVD IO BLN CVAD BLN + ± BLN POMP + + ± + + Capicity 27 64 31 48 84 Conditions – – – 44% Salvage 1 38% 13% Primary refractory Prior BLN 19% Prior 40% CR1 duration < 1 year HSCT 23% Prior HSCT Median age [range] 38 [18–59] 68 [60–81] 73 [66–84] 43 [20–79] 35 [9–87] Response (CR/CRi) 100% 98% 66% 61% 80% MRD negativity by 96% 95% 92% – 80% fow cytometry Duration RFS 76% at 1 year 76% at 3 years DFS 56% at 1 year – 52% at 2 years OS rate 89% at 1 year 54% at 1 years 65% at 1 year Median 10.9 months 39% at 2 years

Ph Philadelphia-chromosome, ALL acute lymphoblastic leukemia, CR complete remission, CRi complete remission with incomplete hematologic recovery, MRD measurable residual disease, OS overall survival, RFS relapse-free survival, mini-HCVD mini-hyper-fractionated cyclophosphamide, vincristine, dexamethasone, IO inotuzumab ozogamicin, HSCT hematopoietic stem cell transplant, hyper-CVAD, hyper-fractionated cyclophosphamide, vincristine, adriamycin, dexamethasone, CVP cyclophosphamide, vincristine, prednisone, SWOG South West Oncology Group, POMP prednisone, vincristine, methotrexate, mercaptopurine

steroid in induction stage and blinatumomab in consoli- and the efcacy which is mainly dependent on the per- dation stage for adult Ph­ + ALL patients of all ages. Te centage and density of the antigen expression, as well general story is that, 5 relapses have been observed (2 as the persistence of antigen expression after repeated hematologic, 2 isolated CNS and 1 nodal), the 12-month immunotherapy exposure. Tis suggests that antibody- OS and DFS are 94.2% and 87.8%. A signifcantly inferior based therapies alone cannot treat ALL. Terefore, we DFS (61.4%, p = 0.01) was observed in IKZF1plus cases. still need HSCT, traditional chemotherapy, TKIs, and So deep molecular response improved throughout ther- even CAR-T therapy to achieve comprehensive treatment apy, but patients carrying IKZF1 plus remains a clinical of ALL. challenge. To know that patients are likely to quickly progress with A recent exciting result via chemo-free induction and each therapy, we need to consider which therapy to use consolidation frst-line strategy with dasatinib and blina- frst or how to sequence or combine the therapies. Tere- tumomab [72] brings out confdence. Te combination fore, clinical trials of low-intensity comparing IO with or shows high incidences of molecular response and sur- without blinatumomab in frst-line and R/R Ph-negative vival, but few toxic efects of grade 3 or higher in Ph-pos- elderly patients are encouraging [73–77]. Retrospective itive ALL. Of all 63 patients (median age 54 years; range studies have demonstrated the safety and efcacy of com- 24–82) enrolled, a complete remission was observed in bining blinatumomab with TKIs, specifcally ponatinib, 98%. At the end of dasatinib induction therapy (d85), in patients with Ph-positive ALL, and several prospective 29% of the patients had a molecular response, and this studies of these combinations are ongoing in both front- percentage increased to 60% after two cycles of blina- line and R/R settings. Highly efective combination thera- tumomab, and higher after additional blinatumomab pies may reduce the need for HSCT in frst remission cycles. At a median follow-up of 18 months, overall for some patients, especially if they can achieve a higher survival was 95% and DFS was 88% Patients who had MRD-negative rate compared to conventional cytotoxic an IKZF1 deletion plus additional genetic aberrations chemotherapy regimens [78, 79]. (CDKN2A or CDKN2B, PAX5, or both [i.e., IKZF1plus]) Besides, with the latest developments and approval had a lower DFS relatively. of CAR-T cell therapy for ALL in recent years, how to rationally use the two new drugs has also attracted sig- Conclusion and future challenges nifcant attention. Up to now, it is still not clear how Novel antibody-based drugs such as blinatumomab and prior blinatumomab therapy afects the ongoing anti- IO are some of the most exciting and promising agents CD19 CAR-T therapy. Tere are also concerns that approved for patients with ALL. However, the present blinatumomab causes the loss of CD19 antigen and dis- study has several limitations that should be noted. Firstly, rupted CD19 membrane export. However, remission the short duration of response and survival outcomes, of such a sequential application is still possible [55, 80, Li and Wang Exp Hematol Oncol (2020) 9:33 Page 9 of 11

81]. Finally, concerning the lack of an optimal target, Competing interests All authors declare that they have no confict of interest. an important limitation of antibody-based therapies need to be acknowledged, which is that the needs for Received: 17 September 2020 Accepted: 19 November 2020 patients with T-cell ALL remain unmet. Several studies are on the march to carry through this important clini- cal question. Novel therapies are needed for the early T-cell precursor subtype, which shows poor outcomes References 1. Kantarjian HM, O’Brien S, Smith TL, Cortes J, Giles FJ, Beran M, et al. Results with conventional chemotherapy [82]. of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute With the development of antibody-based therapies lymphocytic leukemia. J Clin Oncol. 2000;18(3):547–61. such as monoclonal antibodies, ADCs, bispecifc, tri- 2. Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, et al. Induction therapy for adults with acute lymphoblastic leukemia: results specifc, and even multi-specifc antibodies, treatment of more than 1500 patients from the international ALL trial: MRC UKALL options are widely expanded. As discussed above, XII/ECOG E2993. Blood. 2005;106(12):3760–7. antibody-based therapies still face challenges in deter- 3. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehen- sive review and 2017 update. Blood Cancer J. 2017;7(6):e577. mining the best-optimized treatment combination. 4. Wolach O, Amitai I, DeAngelo DJ. Current challenges and opportunities However, successful clinical studies reporting combi- in treating adult patients with Philadelphia-negative acute lymphoblastic nations with other immunotherapies such as CAR-T leukaemia. Br J Haematol. 2017;179(5):705–23. 5. Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. therapy, and T-ALL with the few available drugs, is a Outcome of 609 adults after relapse of acute lymphoblastic leukemia reason to be optimistic that antibody-based treatment (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109(3):944–50. approaches may eventually become a success story in 6. Jabbour E, O’Brien S, Ravandi F, Kantarjian H. Monoclonal antibodies in acute lymphoblastic leukemia. Blood. 2015;125(26):4010–6. ALL therapy. 7. Badar T, Szabo A, Wadleigh M, Liedtke M, Arslan S, Siebenaller C, et al. Real-world outcomes of adult B-cell acute lymphocytic leukemia patients treated with inotuzumab ozogamicin. Clin Lymph Myeloma Leukemia. Abbreviations 2020;20(8):556-60.e2. ALL: Acute lymphoblastic leukemia; BCP-ALL: B-cell precursor acute lympho- 8. Aujla A, Aujla R, Liu D. Inotuzumab ozogamicin in clinical development blastic leukemia; T-ALL: T-cell acute lymphoblastic leukemia; AML: Acute for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Biomark myeloid leukemia; CML: Chronic myelocytic leukemia; ADC: Antibody–drug Res. 2019;7:9. conjugates; R/R: Relapsed or refractory; CR: Complete remission; CRi: Com- 9. Franquiz MJ, Short NJ. Blinatumomab for the treatment of adult B-cell plete remission incomplete hematologic recovery; CRh: Complete response acute lymphoblastic leukemia: toward a new era of targeted immuno- with partial hematologic recovery; OS: Overall survival; CRS: Cytokine release therapy. Biol Targets Ther. 2020;14:23–34. syndrome; BsAb: Bispecifc antibody; MRD: Minimum residual disease; SOC: 10. Zhao J, Song Y, Liu D. Recent advances on blinatumomab for acute Standard of care; CAR-T: Chimeric antigen receptor T-cell; HSCT: Hemopoietic lymphoblastic leukemia. Exp Hematol Oncol. 2019;8:28. stem cell transplantation; CDC: Complement-dependent cytotoxity; ADCC: 11. Yu S, Li A, Liu Q, Yuan X, Xu H, Jiao D, et al. Recent advances of bispecifc Antibody-dependent cellular cytotoxity; TDCC: T cell directed cellular cytotox- antibodies in solid tumors. J Hematol Oncol. 2017;10(1):155. ity; BiTE: Bispecifc T-cell engager; DART​: Dual-afnity re-targeting antibody; 12. Thomas DA, O’Brien S, Jorgensen JL, Cortes J, Faderl S, Garcia-Manero TandAbs: Tendem diabody; VOD: Veno-occlusive disease; IO: Inotuzumab G, et al. Prognostic signifcance of CD20 expression in adults with ozogamicin; PFS: Progression-free survival; RFS: Relapse-free survival; DFS: de novo precursor B-lineage acute lymphoblastic leukemia. Blood. Disease-free survival; Ph−: Philadelphia chromosome negative; Ph+: Philadel- 2009;113(25):6330–7. phia chromosome positive; PBD: Pyrrolobenzodiazepine; PK: Pharmacokinetic; 13. Raponi S, De Propris MS, Intoppa S, Milani ML, Vitale A, Elia L, et al. Flow HL: Hodgkin’s lymphoma; IL-3: Interleukin-3; scFv: Single-chain Fv; TKI: Tyrosine cytometric study of potential target antigens (CD19, CD20, CD22, CD33) kinase inhibitors; APC: Antigen presenting cells. for antibody-based immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leukemia Lymphoma. 2011;52(6):1098–107. Acknowledgements 14. Ribrag V, Koscielny S, Bosq J, Leguay T, Casasnovas O, Fornecker LM, None. et al. Rituximab and dose-dense chemotherapy for adults with Burkitt’s lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet. Authors’ contributions 2016;387(10036):2402–11. LL drafted the manuscript; YW revised the manuscript. All authors read and 15. Hoelzer D, Huettmann A, Kaul F, Irmer S, Jaekel N, Mohren M, et al. approved the fnal manuscript. Immunochemotherapy with Rituximab improves molecular CR rate and outcome In CD20 B-lineage standard and high risk patients; results Funding of 263 CD20 patients+ studied prospectively in GMALL Study 07/2003. The study was supported by grants from the National Natural Science Founda- Blood. 2010;116(21):170.+ tion of China (81830005), National Key Research and Development Program of 16. Thomas DA, O’Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, China (2019YFA0110204), CAMS Innovation Fund for Medical Sciences (CIFMS et al. Chemoimmunotherapy with a modifed hyper-CVAD and rituximab 2016-I2M-1-001). regimen improves outcome in de novo Philadelphia chromosome- negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. Availability of data and materials 2010;28(24):3880–9. The material supporting the conclusion of this review has been included 17. Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, et al. Rituxi- within the article. mab in B-lineage adult acute lymphoblastic leukemia. New Engl J Med. 2016;375(11):1044–53. Ethics approval and consent to participate 18. Wei G, Wang J, Huang H, Zhao Y. Novel immunotherapies for adult This is not applicable for this review. patients with B-lineage acute lymphoblastic leukemia. J Hematol Oncol. 2017;10(1):150. Consent for publication 19. Teeling JL, Mackus WJ, Wiegman LJ, van den Brakel JH, Beers SA, French This is not applicable for this review. RR, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol. 2006;177(1):362–71. Li and Wang Exp Hematol Oncol (2020) 9:33 Page 10 of 11

20. Bazarbachi AH, Yilmaz M, Ravandi F, Thomas DA, Khouri M, Garcia-Manero leukaemic blasts is predictive for outcome and level of residual disease G, et al. A phase 2 study of hyper-CVAD plus ofatumumab as frontline in AML. Eur J Cancer. 1990;45(9):1692–9. therapy in CD20 acute lymphoblastic leukemia (ALL): updated results. J 41. Nakase K, Kita K, Miwa H, Nishii K, Shikami M, Tanaka I, et al. Clinical and Clin Ocol. 2018;36(15+ suppl):7041. prognostic signifcance of cytokine receptor expression in adult acute 21. Raetz EA, Cairo MS, Borowitz MJ, Lu X, Devidas M, Reid JM, et al. Re- lymphoblastic leukemia: interleukin-2 receptor alpha-chain predicts a induction chemoimmunotherapy with epratuzumab in relapsed acute poor prognosis. Leukemia. 2007;21(2):326–32. lymphoblastic leukemia (ALL): Phase II results from Children’s Oncology 42. Burchill MA, Yang J, Vang KB, Farrar MA. Interleukin-2 receptor signaling Group (COG) study ADVL04P2. Pediatr Blood Cancer. 2015;62(7):1171–5. in regulatory T cell development and homeostasis. Immunol Lett. 22. Raetz EA, Cairo MS, Borowitz MJ, Blaney SM, Krailo MD, Leil TA, et al. 2007;114(1):1–8. Chemoimmunotherapy reinduction with epratuzumab in children with 43. Flynn MJ, Hartley JA. The emerging role of anti-CD25 directed thera- acute lymphoblastic leukemia in marrow relapse: a Children’s Oncology pies as both immune modulators and targeted agents in cancer. Br J Group Pilot Study. J Clin Oncol. 2008;26(22):3756–62. Haematol. 2017;179(1):20–35. 23. Jiao Y, Yi M, Xu L, Chu Q, Yan Y, Luo S, et al. CD38: targeted therapy in 44. Dores GM, Devesa SS, Curtis RE, Linet MS, Morton LM. Acute leukemia multiple myeloma and therapeutic potential for solid cancers. Exp Opin incidence and patient survival among children and adults in the Investig Drugs. 2020;29(11):1295–308. United States, 2001–2007. Blood. 2012;119(1):34–43. 24. van de Donk N. Immunomodulatory efects of CD38-targeting antibod- 45. Goldberg AD, Atallah E, Rizzieri D, Walter RB, Chung KY, Spira A, et al. ies. Immunol Lett. 2018;199:16–22. Camidanlumab tesirine, an antibody-drug conjugate, in relapsed/ 25. Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratu- refractory CD25-positive acute myeloid leukemia or acute lymphoblas- mumab depletes CD38 immune regulatory cells, promotes T-cell tic leukemia: a phase I study. Leukemia Res. 2020;95:106385. expansion, and skews T-cell+ repertoire in multiple myeloma. Blood. 46. Gökbuget N, Stanze D, Beck J, Diedrich H, Horst HA, Hüttmann A, 2016;128(3):384–94. et al. Outcome of relapsed adult lymphoblastic leukemia depends on 26. Naik J, Themeli M, de Jong-Korlaar R, Ruiter RWJ, Poddighe PJ, Yuan H, response to salvage chemotherapy, prognostic factors, and perfor- et al. CD38 as a therapeutic target for adult acute myeloid leukemia and mance of stem cell transplantation. Blood. 2012;120(10):2032–41. T-cell acute lymphoblastic leukemia. Haematologica. 2019;104(3):e100–3. 47. Angelova E, Audette C, Kovtun Y, Daver N, Wang SA, Pierce S, et al. 27. Bride KL, Vincent TL, Im SY, Aplenc R, Barrett DM, Carroll WL, et al. Preclini- CD123 expression patterns and selective targeting with a CD123- cal efcacy of daratumumab in T-cell acute lymphoblastic leukemia. targeted antibody-drug conjugate (IMGN632) in acute lymphoblastic Blood. 2018;131(9):995–9. leukemia. Haematologica. 2019;104(4):749–55. 28. Ganzel C, Kharit M, Duksin C, Rowe JM. Daratumumab for relapsed/refrac- 48. Djokic M, Björklund E, Blennow E, Mazur J, Söderhäll S, Porwit A. tory Philadelphia-positive acute lymphoblastic leukemia. Haematologica. Overexpression of CD123 correlates with the hyperdiploid genotype in 2018;103(10):e489–90. acute lymphoblastic leukemia. Haematologica. 2009;94(7):1016–9. 29. Bonda A, Punatar S, Gokarn A, Mohite A, Shanmugam K, Nayak L, et al. 49. Topp MS, Gökbuget N, Stein AS, Zugmaier G, O’Brien S, Bargou RC, Daratumumab at the frontiers of post-transplant refractory T-acute et al. Safety and activity of blinatumomab for adult patients with lymphoblastic leukemia-a worthwhile strategy? Bone Marrow Transpl. relapsed or refractory B-precursor acute lymphoblastic leukaemia: a 2018;53(11):1487–9. multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57–66. 30. Cerrano M, Castella B, Lia G, Olivi M, Faraci DG, Butera S, et al. Immu- 50. Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, nomodulatory and clinical efects of daratumumab in T-cell acute et al. Phase II trial of the anti-CD19 bispecifc T cell-engager blinatu- lymphoblastic leukaemia. Br J Haematol. 2020;191:e21-32. momab shows hematologic and molecular remissions in patients with 31. Touzeau C, Moreau P. Daratumumab for the treatment of multiple relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin myeloma. Expert Opin Biol Ther. 2017;17(7):887–93. Oncol. 2014;32(36):4134–40. 32. Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. 51. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Blinatumomab for minimal residual disease in adults with B-cell precursor et al. Blinatumomab versus chemotherapy for advanced acute lympho- acute lymphoblastic leukemia. Blood. 2018;131(14):1522–31. blastic leukemia. New Engl J Med. 2017;376(9):836–47. 33. Piccaluga PP, Arpinati M, Candoni A, Laterza C, Paolini S, Gazzola A, et al. 52. Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp Surface antigens analysis reveals signifcant expression of candidate MS, et al. Complete hematologic and molecular response in adult targets for immunotherapy in adult acute lymphoid leukemia. Leukemia patients with relapsed/refractory Philadelphia chromosome-positive Lymphoma. 2011;52(2):325–7. B-precursor acute lymphoblastic leukemia following treatment with 34. de Vries JF, Zwaan CM, De Bie M, Voerman JS, den Boer ML, van Dongen blinatumomab: results from a phase II, single-arm, multicenter study. J JJ, et al. The novel calicheamicin-conjugated CD22 antibody inotuzumab Clin Oncol. 2017;35(16):1795–802. ozogamicin (CMC-544) efectively kills primary pediatric acute lympho- 53. Aldoss I, Song J, Stiller T, Nguyen T, Palmer J, O’Donnell M, et al. Cor- blastic leukemia cells. Leukemia. 2012;26(2):255–64. relates of resistance and relapse during blinatumomab therapy for 35. Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gokbuget relapsed/refractory acute lymphoblastic leukemia. Am J Hematol. N, et al. Inotuzumab ozogamicin versus standard of care in relapsed 2017;92(9):858–65. or refractory acute lymphoblastic leukemia: fnal report and long-term 54. Köhnke T, Krupka C, Tischer J, Knösel T, Subklewe M. Increase of PD-L1 survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. expressing B-precursor ALL cells in a patient resistant to the CD19/ 2019;125(14):2474–87. CD3-bispecifc T cell engager antibody blinatumomab. J Hematol 36. Hartley JA. The development of pyrrolobenzodiazepines as antitumour Oncol. 2015;8:111. agents. Exp Opin Investig Drugs. 2011;20(6):733–44. 55. Braig F, Brandt A, Goebeler M, Tony HP, Kurze AK, Nollau P, et al. 37. Hartley JA, Flynn MJ, Bingham JP, Corbett S, Reinert H, Tiberghien A, et al. Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia Pre-clinical pharmacology and mechanism of action of SG3199, the pyr- may be mediated by disrupted CD19 membrane trafcking. Blood. rolobenzodiazepine (PBD) dimer warhead component of antibody-drug 2017;129(1):100–4. conjugate (ADC) payload tesirine. Sci Rep. 2018;8(1):10479. 56. Portell CA, Wenzell CM, Advani AS. Clinical and pharmacologic aspects 38. Zammarchi F, Corbett S, Adams L, Tyrer PC, Kiakos K, Janghra N, et al. of blinatumomab in the treatment of B-cell acute lymphoblastic leuke- ADCT-402, a PBD dimer-containing antibody drug conjugate targeting mia. Clin Pharmacol. 2013;5(Suppl 1):5–11. CD19-expressing malignancies. Blood. 2018;131(10):1094–105. 57. Klinger M, Brandl C, Zugmaier G, Hijazi Y, Bargou RC, Topp MS, 39. Jain N, Stock W, Zeidan A, Atallah E, McCloskey J, Hefner L, et al. et al. Immunopharmacologic response of patients with B-lineage Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in acute lymphoblastic leukemia to continuous infusion of T cell- relapsed/refractory B-cell acute lymphoblastic leukemia. Blood Adv. engaging CD19/CD3-bispecifc BiTE antibody blinatumomab. Blood. 2020;4(3):449–57. 2012;119(26):6226–33. 40. Terwijn M, Feller N, van Rhenen A, Kelder A, Westra G, Zweegman 58. Wolf E, Hofmeister R, Kufer P, Schlereth B, Baeuerle PA. BiTEs: bispecifc S, et al. Interleukin-2 receptor alpha-chain (CD25) expression on antibody constructs with unique anti-tumor activity. Drug Discov Today. 2005;10(18):1237–44. Li and Wang Exp Hematol Oncol (2020) 9:33 Page 11 of 11

59. Rader C. DARTs take aim at BiTEs. Blood. 2011;117(17):4403–4. with CVP (cyclophosphamide, vincristine, prednisone) for relapsed/refrac- 60. Moore PA, Zhang W, Rainey GJ, Burke S, Li H, Huang L, et al. Application tory CD22 acute leukemia. Blood. 2019;134(Suppl 1):227. of dual afnity retargeting molecules to achieve optimal redirected T-cell 74. Advani AS,+ Moseley A, O’Dwyer KM, Wood B, Fang M, Wieduwilt MJ, killing of B-cell lymphoma. Blood. 2011;117(17):4542–51. et al. Results of SWOG 1318: a Phase 2 trial of blinatumomab followed 61. Yang F, Wen W, Qin W. Bispecifc antibodies as a development platform by pomp (prednisone, vincristine, methotrexate, 6-mercaptopurine) for new concepts and treatment strategies. Int J Mol Sci. 2016;18(1):48. maintenance in elderly patients with newly diagnosed Philadelphia 62. Walseng E, Nelson CG, Qi J, Nanna AR, Roush WR, Goswami RK, et al. chromosome negative B-cell acute lymphoblastic leukemia. Blood. Chemically programmed bispecifc antibodies in diabody format. J Biol 2018;132(Suppl 1):33. Chem. 2016;291(37):19661–73. 75. Richard-Carpentier G, Kantarjian HM, Short NJ, Ravandi F, Ferrajoli A, 63. Reusch U, Harrington KH, Gudgeon CJ, Fucek I, Ellwanger K, Weichel Schroeder HM, et al. Updated Results from the phase II study of hyper- M, et al. Characterization of CD33/CD3 tetravalent bispecifc tandem CVAD in sequential combination with blinatumomab in newly diag- diabodies (TandAbs) for the treatment of acute myeloid leukemia. Clin nosed adults with B-cell acute lymphoblastic leukemia (B-ALL). Blood. Cancer Res. 2016;22(23):5829–38. 2019;134(Suppl 1):3807. 64. Reusch U, Burkhardt C, Fucek I, Le Gall F, Le Gall M, Hofmann K, et al. A 76. Sasaki K, Kantarjian HM, Ravandi F, Short NJ, Kebriaei P, Huang X, et al. novel tetravalent bispecifc TandAb (CD30/CD16A) efciently recruits NK Sequential combination of low-intensity chemotherapy (mini-hyper- cells for the lysis of CD30 tumor cells. mAbs. 2014;6(3):728–39. CVD) plus Inotuzumab Ozogamicin with or without Blinatumomab 65. Compte M, Alvarez-Cienfuegos+ A, Nuñez-Prado N, Sainz-Pastor N, Blanco- in Patients with relapsed/refractory Philadelphia chromosome- Toribio A, Pescador N, et al. Functional comparison of single-chain and negative acute lymphoblastic leukemia (ALL): a phase 2 trial. Blood. two-chain anti-CD3-based bispecifc antibodies in gene immunotherapy 2018;132(Suppl 1):553. applications. Oncoimmunology. 2014;3:e28810. 77. Short NJ, Kantarjian HM, Ravandi F, Huang X, Jain N, Sasaki K, et al. 66. Wu L, Seung E, Xu L, Rao E, Lord DM, Wei RR, et al. Trispecifc antibodies Updated results of a Phase II. Study of reduced-intensity chemotherapy enhance the therapeutic efcacy of tumor-directed T cells through T cell with mini-hyper-CVD in combination with inotuzumab ozogamicin with receptor co-stimulation. Nature Cancer. 2020;1(1):86–98. or without blinatumomab, in older adults with newly diagnosed Phila- 67. Jabbour E, Short NJ, Jorgensen JL, Yilmaz M, Ravandi F, Wang SA, et al. delphia chromosome-negative acute lymphoblastic leukemia. Blood. Diferential impact of minimal residual disease negativity according 2019;134(Suppl 1):823. to the salvage status in patients with relapsed/refractory B-cell acute 78. Short NJ, Jabbour E, Sasaki K, Patel K, O’Brien SM, Cortes JE, et al. Impact lymphoblastic leukemia. Cancer. 2017;123(2):294–302. of complete molecular response on survival in patients with Phila- 68. Assi R, Kantarjian H, Short NJ, Daver N, Takahashi K, Garcia-Manero delphia chromosome-positive acute lymphoblastic leukemia. Blood. G, et al. Safety and efcacy of blinatumomab in combination with a 2016;128(4):504–7. tyrosine kinase inhibitor for the treatment of relapsed Philadelphia 79. Berry DA, Zhou S, Higley H, Mukundan L, Fu S, Reaman GH, et al. Asso- chromosome-positive leukemia. Clin Lymphoma Myeloma Leukemia. ciation of minimal residual disease with clinical outcome in pediatric 2017;17(12):897–901. and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol. 69. Short NJ, Kantarjian H, Jabbour E, Ravandi F. Which tyrosine kinase 2017;3(7):e170580. inhibitor should we use to treat Philadelphia chromosome-positive 80. Ruella M, Maus MV. Catch me if you can: leukemia escape after acute lymphoblastic leukemia? Best Pract Res Clin Haematol. CD19-directed t cell immunotherapies. Comput Struct Biotechnol J. 2017;30(3):193–200. 2016;14:357–62. 70. Jain N, Cortes JE, Ravandi F, Konopleva M, Alvarado Y, Kadia T, et al. 81. Slaney CY, Wang P, Darcy PK, Kershaw MH. CARs versus BiTEs: a compari- Inotuzumab ozogamicin in combination with bosutinib for patients with son between T cell-redirection strategies for cancer treatment. Cancer relapsed or refractory Ph ALL or CML in lymphoid blast phase. Blood. Discov. 2018;8(8):924–34. 2017;130(Suppl 1):143. + 82. Jain N, Lamb AV, O’Brien S, Ravandi F, Konopleva M, Jabbour E, et al. 71. Chiaretti S, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo C, et al. Dasat- Early T-cell precursor acute lymphoblastic leukemia/lymphoma inib–Blinatumomab combination for the front-line treatment of adult (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype. Blood. Ph ALL patients updated results of the gimema LAL2116 D-Alba trial. 2016;127(15):1863–9. Blood.+ 2019;134(Suppl 1):740. 72. Foà R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo MC, et al. Dasatinib– Blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. Publisher’s Note New Engl J Med. 2020;383(17):1613–23. Springer Nature remains neutral with regard to jurisdictional claims in pub- 73. Advani AS, Moseley A, Liedtke M, O’Donnell MR, Aldoss I, Mims MP, et al. lished maps and institutional afliations. SWOG 1312 fnal results: a Phase 1 trial of inotuzumab in combination

Ready to submit your research ? Choose BMC and benefit from:

• fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations • maximum visibility for your research: over 100M website views per year

At BMC, research is always in progress.

Learn more biomedcentral.com/submissions